Successful treatment of cancer, including primary and metastatic solid tumors, remains an unfulfilled medical goal, despite increased understanding of the molecular biology of tumor cells and the availability of an increased number of potential therapeutic agents.
One problem in the treatment of cancers is that an effective dose of a wide variety of potential chemotherapeutic agents is restricted by the non-selective, highly toxic effect of these agents on normal tissues. As a result, many patients suffer from the side effects of chemotherapy without reaping the benefits of the treatment. A related problem is an often poor, and thus therapeutically-deficient, delivery of the chemotherapeutic drug specifically to the tumor. Thus, there is a necessity to develop more specific and less toxic cancer therapies.
Another problem is related to the identification of the cancer for proper treatment. Typically the cancerous tissue is examined under a microscope to determine the cell type, enabling a physician to determine if that type of cell is normally found in the part of the body from which the tissue sample was taken, or whether it is metastatic. The use of immunohistochemistry enables identification of many of these metastases. It is theorized that metastasis always coincides with a primary cancer, and, as such, is a tumor that started from a cancer cell or cells in another part of the body. However, over 10% of patients will have metastases without a primary tumor found. In these cases, the primary tumor as “unknown” or “occult,” and the patient is said to have a cancer of unknown primary origin. It is estimated that 3% of all cancers are of unknown primary origin. This can be problematic because effective treatment of a cancer begins with its identification.
Although the cells in a metastatic tumor resemble those in the primary tumor, difficulties in treatment can arise because the metastatic cancer may have different characteristics than the primary cancer. Some cancers have been found to have a “metastatic signature”, or differences in the expression of a subset of genes between the primary cancer and its metastasis. Accordingly, because of these genetic differences, a physician cannot assume that successful treatment of a primary cancer will be the same as treatment of a metastatic cancer, and vice versa. Thus there remains a need for effective treatments for both metastatic and primary cancers.
Further problems concern the treatment of inoperable cancers. Some of these inoperable cancers remain incurable by chemotherapy. For example, cholangiocarcinoma, a cancer of the bile ducts which drain bile from the liver into the small intestine, is considered to be an incurable and rapidly lethal disease unless all of its tumors can be fully resected. For non-resectable cases, the 5-year survival rate is 0% where the disease is inoperable because distal lymph nodes show metastases, and less than 5% in general. Overall median duration of survival is less than 6 months in inoperable, untreated, otherwise healthy patients with tumors involving the liver. A steady increase in the incidence of intrahepatic cholangiocarcinoma has been documented over the past several decades in North America, Europe, Asia, and Australia. Unfortunately, most patients have advanced and inoperable disease at the time of diagnosis. In these patients, their disease can be managed, though never cured, with chemotherapy and/or radiation therapy.
Similarly, transitional cell carcinoma (TCC, also termed urothelial cell carcinoma or UCC) is another problematic cancer to treat. TCC typically occurs in the urinary system, including the kidney, bladder, ureter, urethra, and/or urachus, and arises from the transition epithelium, a tissue lining the inner surface of these hollow organs. TCC is the most common tumor of the renal pelvis. Over 70,000 cases of bladder cancer are diagnosed annually in the United States. Upper urinary tract TCC is estimated to occur in 5% of all urothelial cancers and in less than 10% of renal tumors. Evidence indicates that the frequency of upper urinary tract malignancies is increasing. Treatment for limited stage TCC is surgical resection of the tumor, but reoccurrence is common due to the presence of occult micrometastases at diagnosis. While five-year survival rates in patients with invasion beyond muscle can approach 40 percent, survival for patients with lymph node involvement does not exceed 10 percent. Chemotherapy for TCC consisting of the “MVAC” regimen (methotrexate, vinblastine, adriamycin and cisplatin) has been used with limited success.
Thus, there remains a need for more effective chemotherapeutic treatment of metastatic carcinoma, and for cholangiocarcinoma and TCC, especially in cases of inoperable disease.